Thai HIV Research Articles

P-580. A randomized controlled trial evaluating virologic and renal outcomes after switching from TDF/FTC/EFV to TDF/3TC/DTG (TLD) versus DTG+3TC in virologically suppressed Thai PWH – a pilot study

Abstract Background TDF/3TC/DTG (TLD) has been adopted as the first line of therapy for all PWH according to the WHO 2019 and Thai HIV guidelines, hence, PWH in Thailand on TDF/FTC/EFV are opted for a switch to TLD. However, switching to DTG+3TC is not inferior to TDF-based ART in terms of efficacy, but with more favorable renal safety. In this study, we compared estimated glomerular filtration rates (eGFR), virological and immunological response, and metabolic parameters among PWH currently receiving TDF+FTC or 3TC+EFV who are switched to TLD versus DTG+3TC. Figure 1. Flow diagram of eligible cases Methods We enrolled virologically suppressed PWH age ≥18 years currently on TDF+FTC or 3TC+EFV and randomly switched to TLD or DTG+3TC at 2 tertiary care hospitals. The primary outcome was a change of eGFR calculated by cystatin C at 24 weeks. Secondary outcomes were changes in eGFR calculated by creatinine, LDL, body weight, and BMI at 24 weeks. Figure 2. Comparison of eGFR changes calculated by cystatin C (left Y axis) and creatinine (right Y axis) from baseline (pre-switch) to the 2nd follow-up (post-switch) among participants who were switched to TLD versus DTG+3TC (A). Changes of eGFR calculated by cystatin C from pre-switch to post-switch in the TLD group (B) and DTG+3TC group (C). The differences in change for each group were shown in the scatter dot plot on the right column within each figure. The error bar represents a 95% confidence interval of the mean change, while the thick line in the middle of the bar represents the mean. Results There were 16 participants, with 8 assigned to the TLD and 8 to the DTG+3TC group (Figure 1). There were 69% male with a mean age of 41 years (Table 1). The mean time from HIV diagnosis to switching was 7.1 years. The decrement of the eGFR by cystatin C and creatinine was higher in the TLD than in the DTG+3TC group: mean difference 5.15 ml/min/1.73 m2 (95% CI -12.06 to 22.35) (p=0.532) and 4.01 ml/min/1.73 m2 (95% CI -3.58 to 11.59) (p=0.277), respectively (Figure 2A). However, within each group, there was a significant reduction of eGFR by cystatin C in the TLD group: mean changes -13.19 (95% CI -18.53 to -7.84) (p< 0.001) (Figure 2B). There was no significant reduction of eGFR by cystatin C in the DTG+3TC group: mean changes -8.04 (95% CI -26.24 to 10.16) (p=0.331) (Figure 2C). In the sensitivity analysis excluding outliers, there was a significant reduction of eGFR by cystatin C after switching to the TLD than to the DTG+3TC: mean difference of 15.47 (95% CI 4.81 – 26.13) (p=0.008). All participants in both groups achieved virological suppression. There was insignificant BMI, LDL, and CD4 change between the two groups (Figure 3). Figure 3. Comparison of mean changes for (A) BMI; (B) LDL; and (C) CD4 percentage (CD4%) from baseline to the 2nd follow-up after switching between the two groups. The error bar represents 95% confidence interval of mean changes calculated from paired T-tests within each group. Conclusion There was a trend toward a higher reduction of eGFR by cystatin C among PWH who were switched to TLD than to the DTG+3TC. Changes in the LDL and BMI were comparable. Dual therapy with DTG+3TC may be a preferred option as a switching therapy over TLD in selected cases with renal safety concerns. Table 1. Baseline characteristics of all participants. Disclosures All Authors: No reported disclosures

Give the community the tools and they will help finish the job: key population-led health services for ending AIDS in Thailand.

Give the community the tools and they will help finish the job: key population-led health services for ending AIDS in Thailand.

Dosage Optimization of Efavirenz Based on a Population Pharmacokinetic–Pharmacogenetic Model of HIV-infected Patients in Thailand

PurposeEfavirenz exhibits high interindividual variability in plasma concentrations, leading to unpredictable efficacy and toxicity. Polymorphism of CYP2B6 516G > T has been found to predominantly contribute to efavirenz variability. However, dosage recommendations incorporating CYP2B6 516G > T polymorphism have not been investigated in the Thai population. This study aimed to develop a population model of the pharmacokinetic properties of efavirenz, and to investigate the impact of patients' characteristics and CYP2B6 516G > T polymorphism on the pharmacokinetic properties of efavirenz. Model-based simulations were performed to provide genotype-based dosage optimization in a Thai population. MethodsPlasma efavirenz concentrations measured at 12 h post-dose in 360 Thai HIV-infected patients with and without tuberculosis were analyzed by the nonlinear mixed-effects modeling approach. A 1-compartment model with first-order absorption and elimination was used for describing the pharmacokinetic properties of efavirenz. FindingsThe allele frequency of CYP2B6 516G > T was 34.17%. The efavirenz oral clearance were 11.9, 8.0, and 2.8 L/h in patients weighing 57 kg and having the CYP2B6 516 GG, 516 GT, and 516 TT genotypes, respectively. The use of rifampicin increased efavirenz oral clearance by 28%. The results from the simulations suggest that efavirenz dosages of 400, 300, and 100 mg once daily in Thai HIV mono-infected patients, and 800, 600, and 200 mg once daily in HIV/tuberculosis co-infected patients carrying CYP2B6 516 GG, 516 GT, and 516 TT, respectively. ImplicationThe results from this study provide a rationale for efavirenz dose adjustment based on CYP2B6 516G > T polymorphism in Thai HIV-infected patients, which could help to improve treatment outcomes in this population. ClinicalTrials.gov identifier: NCT01138267.

CD4/CD8 ratio normalization rates and low ratio as prognostic marker for non-AIDS defining events among long-term virologically suppressed people living with HIV

BackgroundImmune restoration is often incomplete after ART in HIV patients, both quantitatively and qualitatively. We studied the incidence and probability of CD4/CD8 normalization in an adult Thai HIV cohort and explored the predictive value of the ratio for developing of non-AIDS defining events (NAEs).MethodsWe analyzed data from HIV-infected Thai adults between 1996 and 2017 in the HIV-NAT 006 prospective long-term cohort in Bangkok, Thailand. Normalization was defined as CD4/CD8 ratio ≥ 1 on two consecutive visits, and normalization probability was calculated using the Kaplan–Meier method. NAEs were a composite endpoint including cardiovascular or cerebrovascular diseases, chronic kidney diseases, non-AIDS defining malignancies and death. Multivariate Cox regression was used to evaluate demographic, disease and treatment characteristics associated with CD4/CD8 ratio normalization and NAEs.ResultsA total of 800 ART-naïve patients with baseline CD4/CD8 ratio of < 0.8 who started combination ART, and had sustained virological suppression were enrolled. Participants were on ART for a median of 8.9 years and virologically suppressed for 6.1 years. The probabilities of CD4/CD8 normalization at 2, 5 and 10 years after virological suppression were 5.1%, 18.6% and 39.1%, respectively. Factors associated with normalization in multivariate analysis were female sex (hazard ratio [HR]: 2.47, 95% CI 1.71–3.56, p < 0.001) and baseline CD4 counts ≥ 350 cells/mm3 (HR: 3.62, 95% CI 2.36–5.55), p < 0.001) vs. < 200 cells/mm3 as reference. The second analysis explored the predictive value of CD4/CD8 ratio for NAEs. Older age (HR: 1.09, 95% CI 1.05–1.13, p < 0.01) and current CD4/CD8 ratio < 0.3 (HR: 3.02, 95% CI 1.27–7.21, p = 0.01) or between 0.3 and 0.45 (HR: 2.03, 95% CI 1.03–3.98, p = 0.04) vs. > 0.45 were independently associated with higher risk of progression to NAEs in the multivariate analysis.ConclusionsOur findings showed that complete immune recovery is uncommon in an Asian setting and earlier ART initiation at higher CD4 counts may have increased the ratio sooner. The findings demonstrate the use of CD4/CD8 ratio as a prognostic marker for clinical progression of NAEs.Trial registration HIV-NAT 006 cohort, clinical trial number: NCT00411983

Antibody-Dependent Cellular Cytotoxicity Activity of Effector Cells from HIV-Infected Elite and Viral Controllers

Carriage of alleles encoding certain inhibitory natural killer (NK) cell receptor/HLA ligand KIR3DL1/HLA-B combinations is associated with protection from HIV infection and slow time to AIDS, implicating NK cells in HIV control. NK cells also mediate antibody-dependent cellular cytotoxicity (ADCC). ADCC has been identified as a correlate of protection in secondary analyses of the modestly protective RV144 Thai HIV vaccine trial. In ADCC, HIV envelope (Env)-specific antibodies (Abs) bridge HIV-infected or gp120-coated target cells and NK cells expressing CD16 receptors for Ab Fc domains. CD16 engagement activates NK cells to secrete cytokines/chemokines, degranulate, deliver granzyme B (GrB) to target cells, and cytolysis. A subset of HIV+ subjects, known as slow progressors (SPs), maintains low-level viremia without treatment. HIV+ SPs versus progressors have higher titers and/or a greater breadth of ADCC-competent Abs. Investigations of the functional capacity of NK effector cells following CD16 engagement in HIV+ subjects are lacking. We used the ADCC-GranToxiLux (ADCC-GTL) assay to assess the frequency of GrB+ (%GrB+) cells generated by effector cells from 37 HIV+ SPs and 15 progressors to gp120-coated CEM.NKr.CCR5 target cells in the presence of anti-Env Abs. Subject groups were stratified according to whether or not they carried educating KIR3DL1/HLA-B combinations able to confer NK cells with functional potential. No differences were observed in %GrB+ target cells generated by effector cells from carriers of educating versus noneducating KIR3DL1/HLA-B pairs. The absence of an effect of NK cell education on this readout may be due to loss of the ability of educated NK cells from SPs to respond to Ab-dependent stimulation and/or the lower frequency of KIR3DL1+ than KIR3DL1- NK cells that coexpress CD16. That KIR/HLA genotypes have minimal impact on interindividual differences in ADCC potency has relevance for therapeutic interventions that target ADCC for HIV control.

The effect of KIR2D-HLA-C receptor-ligand interactions on clinical outcome in a HIV-1 CRF01_AE-infected Thai population.

Class I human leukocyte antigen (HLA) alleles interact with both cytotoxic T lymphocytes through their T-cell receptors, and natural killer cells through their killer immunoglobulin-like receptors (KIRs). Compared with the reported protective effect of KIR3DL1/S1-HLA-Bw4 interactions in HIV-infected patients, the effect of KIR2D-HLA-C combinations on HIV control remains unclear. Here, we investigate the effect of KIR2D-HLA-C combinations on HIV disease progression. We performed a cross-sectional and longitudinal analysis of a Thai HIV cohort. Two hundred and nine HIV-1 CRF01_AE-infected, treatment-naive Thai patients (CD4 T-cell counts of >200/μl) and 104 exposed seronegatives were studied. The effect of KIR-HLA receptor-ligand combinations on viral transmission and survival rate was statistically analyzed. We found the following results: higher frequency of patients expressing both KIR2DL3 and HLA-C1 among infected patients compared with exposed seronegative (odds ratio 4.8, P = 0.004), higher viral load in patients expressing HLA-C1 with KIR2DL3 compared with those without this receptor-ligand combination (median 4.8 vs. 4.2 log copies/ml, P = 0.033), higher numbers of KIR2DL3-HLA-C1 interactions was associated with a higher viral load (β = 0.13, P = 0.039 by linear regression model), and higher mortality rate in carriers of the KIR2DL3-HLA-C1 combination (adjusted hazard ratio 1.9, P = 0.012 by Cox hazard model). We have identified a deleterious effect of the KIR2DL3-HLA-C1 receptor-ligand combination on HIV clinical outcomes in a Thai cohort. Further investigation into mechanisms underlying this susceptibility may aid the understanding of the role of natural killer cells in HIV disease control and pathogenesis.

Genome-Wide Association Study of HIV-Related Lipoatrophy in Thai Patients: Association of a DLGAP1 Polymorphism with Fat Loss.

HIV-related lipoatrophy (LA) is a major adverse drug effect among HIV patients receiving the antiretroviral drug stavudine (d4T) in Southeast Asia. Although the development of LA could be observed in almost all HIV patients administered d4T for extended periods, there is considerable variation in the duration required to develop LA within this patient population. This study aimed to identify host genetic polymorphisms affecting the rate of LA onset in Thai HIV patients. We performed a genome-wide association study of HIV-related LA among patients at the Bamrasnaradura Infectious Diseases Institute, Thailand. Genotypes of HIV patients who developed LA within 2 years of treatment were compared with those of patients who did not develop LA after at least 4 years of treatment (non-LA patients). Genotypes of 49 LA and 92 non-LA patients at 578,525 single nucleotide polymorphisms (SNPs) were determined by Illumina bead arrays. The TaqMan real-time PCR method was used in a replication study. Five SNPs in the bead arrays, which showed the lowest p values in a comparison of LA with non-LA patients, were further tested in independent and sex-matched subpopulations consisting of 95 LA and 95 non-LA patients. This replication study revealed a significant association of LA with an SNP (rs12964965) in the gene encoding the Disks Large Homolog-Associated Protein 1 (DLGAP1), even after the correction for five multiple comparisons. These results strongly suggested involvement of the DLGAP1 gene product in the development of LA in Thai HIV patients.

Phenotype, genotype, and antibiotic susceptibility of Swedish and Thai oral isolates of Staphylococcus aureus

ObjectiveThe present study investigated phenotypes, virulence genotypes, and antibiotic susceptibility of oral Staphylococcus aureus strains in order to get more information on whether oral infections with this bacterium are associated with certain subtypes or related to an over-growth of the S. aureus variants normally found in the oral cavity of healthy carriers.Materials and methodsA total number of 157 S. aureus strains were investigated. Sixty-two strains were isolated from Swedish adults with oral infections, 25 strains were from saliva of healthy Swedish dental students, and 45 strains were from tongue scrapings of HIV-positive subjects in Thailand, and 25 Thai strains from non-HIV controls. The isolates were tested for coagulase, nitrate, arginine, and hemolysin, and for the presence of the virulence genes: hlg, clfA, can, sdrC, sdrD, sdrE, map/eap (adhesins) and sea, seb, sec, tst, eta, etb, pvl (toxins). MIC90 and MIC50 were determined by E-test against penicillin V, oxacillin, amoxicillin, clindamycin, vancomycin, fusidic acid, and cefoxitin.ResultsWhile the hemolytic phenotype was significantly (p<0.001) more common among the Thai strains compared to Swedish strains, the virulence genes were found in a similar frequency in the S. aureus strains isolated from all four subject groups. The Panton-Valentine leukocidin (PVL) genotype was found in 73–100% of the strains. More than 10% of the strains from Swedish oral infections and from Thai HIV-positives showed low antibiotic susceptibility, most commonly for clindamycin. Only three methicillin-resistant S. aureus (MRSA) strains were identified, two from oral infections and one from a Thai HIV patient.ConclusionsS. aureus is occasionally occurring in the oral cavity in both health and disease in Sweden and Thailand. It is therefore most likely that S. aureus in opportunistic oral infections originate from the oral microbiota. S. aureus should be considered in case of oral infections and complaints and the antibiotic susceptibility (including MRSA) should regularly be checked. The frequent presence of S. aureus, although in low numbers among students and staff, emphasizes the importance of standard infection control precautions and of using diagnostic test in the dental clinic.

Polymorphisms of ABCC2, ABCC4, ABCC10 andSLC22A6 in Thai HIV - infected patients

Polymorphisms of ABCC2, ABCC4, ABCC10 andSLC22A6 in Thai HIV - infected patients

From transmission to transition: lessons learnt from the Thai paediatric antiretroviral programme.

BackgroundThe Thai HIV programme is a leader in the public health approach to HIV treatment. Starting at transmission of HIV and ending with transition to adult services this paper assesses the paediatric HIV treatment continuum from three perspectives: service-user, provider and policy maker, to understand what works well and why.MethodsA qualitative research design was used to assess and triangulate the stakeholder perspectives. Semi-structured interviews were conducted with ART service-users (n = 35), policy actors (n = 20); telephone interviews with prior caregivers of orphans (n = 10); and three focus group discussions with service-providers (hospital staff and volunteers) from a district, provincial and a university hospital.FindingsChildren accessing HIV care were often orphaned, cared for by elderly relatives and experiencing multiple vulnerabilities. Services were divided into three stages, 1. Diagnosis and linkage: Despite strong policies there were supply and demand-side gaps in the prevention of mother-to-child transmission ‘cascade’ preventing early diagnosis and/or treatment. 2. Maintenance on ART - Children did well on treatment; caregivers took adherence seriously and valued the quality of services. Drug resistance, adherence and psychosocial issues were important concerns from all perspectives. 3. Adolescents and transition: Adolescent service-users faced greater complexity in their physical and emotional lives for which providers lacked skills; transition from the security of paediatric clinic was a daunting prospect. Dedicated healthcare providers felt they struggled to deliver services that met service-users' diverse needs at all stages. Child- and adolescent-specific elements of HIV policy were considered low priority.ConclusionsUsing the notion of the continuum of care a number of strengths and weaknesses were identified. Features of paediatric services need to evolve alongside the changing needs of service users. Peer-support volunteers have potential to add continuity and support at all stages. It is critical that adolescents receive targeted support, particularly during transition to adult services.

Usefulness of Patient-Generated Index for HIV to Measure Individual Quality of Life: A Study from Thailand

ObjectivesTo measure health-related quality of life (HRQOL) in Thai HIV patients using the patient-generated index for HIV (PGI-HIV) and to compare the psychometric properties of the PGI-HIV with those of the EuroQol five-dimensional (EQ-5D) questionnaire and the Medical Outcome Study HIV Health Survey in terms of practicality, reliability, validity, and responsiveness. MethodsIn this study, two rounds of interviews were carried out in HIV outpatients who met the eligibility criteria and attended the HIV Clinic of Warinchamrap Hospital between January and March 2010. The patients were interviewed using a data collection form and three HRQOL measures (the PGI-HIV, the EQ-5D questionnaire, and the Medical Outcome Study HIV Health Survey) to assess the practicality and validity. The second interview was performed to check the test-retest reliability and responsiveness. ResultsA total of 210 patients completed the study. They were mostly women (69.5%), with a mean age of 39.2 ± 11.1 years. The majority with the US Centers for Disease Control and Prevention clinical stage C took the current antiretroviral drugs within 1 year. The average PGI score was about 0.60, implying HIV/AIDS and antiretroviral drug therapy decreased the patients’ quality of life by 40% from their healthy life. Three mostly cited impact domains were hyperlipidemia, lipid maldistribution and lipodystrophy, and hepatitis. The PGI-HIV was considered as practical, with a mean difficulty score of 3.7 ± 0.8, highly reliable (intraclass correlation coefficient = 0.75; P < 0.001), and responsive to HRQOL changes (effect size = 0.81; standardized response mean = 0.99), but not valid when compared with CD4 levels and viral loads (all Pearson’ r < 0.2; P > 0.05). ConclusionsThe PGI-HIV was used to measure the individual HRQOL in a Thai sample of HIV-positive patients. It proves to be practical, highly reliable, and very responsive to changes in patients’ HRQOL.

Understanding the efficacy variables of an HIV vaccine trial

In The Lancet Infectious Diseases, Merlin Robb and colleagues1 report results from a post-hoc analysis of the Thai HIV vaccine trial RV 144. The Article provides important insights into behavioural and temporal variables that might have affected the protective efficacy of the vaccine.

The Thai Phase III Trial (RV144) Vaccine Regimen Induces T Cell Responses That Preferentially Target Epitopes within the V2 Region of HIV-1 Envelope

The Thai HIV phase III prime/boost vaccine trial (RV144) using ALVAC-HIV (vCP1521) and AIDSVAX B/E was, to our knowledge, the first to demonstrate acquisition efficacy. Vaccine-induced, cell-mediated immune responses were assessed. T cell epitope mapping studies using IFN-γ ELISPOT was performed on PBMCs from HIV-1-uninfected vaccine (n = 61) and placebo (n = 10) recipients using HIV-1 Env peptides. Positive responses were measured in 25 (41%) vaccinees and were predominantly CD4(+) T cell-mediated. Responses were targeted within the HIV Env region, with 15 of 25 (60%) of vaccinees recognizing peptides derived from the V2 region of HIV-1 Env, which includes the α(4)β(7) integrin binding site. Intracellular cytokine staining confirmed that Env responses predominated (19 of 30; 63% of vaccine recipients) and were mediated by polyfunctional effector memory CD4(+) T cells, with the majority of responders producing both IL-2 and IFN-γ (12 of 19; 63%). HIV Env Ab titers were higher in subjects with IL-2 compared with those without IL-2-secreting HIV Env-specific effector memory T cells. Proliferation assays revealed that HIV Ag-specific T cells were CD4(+), with the majority (80%) expressing CD107a. HIV-specific T cell lines obtained from vaccine recipients confirmed V2 specificity, polyfunctionality, and functional cytolytic capacity. Although the RV144 T cell responses were modest in frequency compared with humoral immune responses, the CD4(+) T cell response was directed to HIV-1 Env and more particularly the V2 region.

An HIV-1 clade A/E DNA prime, recombinant fowlpox virus boost vaccine is safe, but non-immunogenic in a randomized phase I/IIa trial in Thai volunteers at low risk of HIV infection

NCHECR is funded by the Australian Government Department of Health & Ageing and is affiliated with the Faculty of Medicine, The University of New South Wales. The vaccines were designed with the assistance of NIH-NIAID-DAIDS HVDDT Award N01-AI-05395. The authors would like to thank Wadchara Pumpradit for his assistance in the preparation and initial drafting of trial protocols and regulatory documents. We also wish to thank members of the Australia Thai HIV Vaccine Consortium including the CSIRO, Australian National University, University of Melbourne, Australian Federation of AIDS Organisations, National Centre in HIV Social Research, University of New South Wales for the design and manufacture of vaccines and assistance with study protocol drafting and initiation. We would like to acknowledge Ormrudee Rit-im, Wendy Lee, Noorul Absar, Charles Tran, Pitch Boonrak and Ekkasit Thodsanit for database and statistical assistance, Nounpen Sangthong, Narumon Subsri, Kanitta Pussadee and Peeraporn Keaw-on for clinical care, Parinya Sutheerasak for pharmacy expertise and Meeling Munier, Kate Merlin, Supranee Buranapraditkun, Pornsupa Chatkulkawin for their laboratory input. Salaries for those working in the Vaccine and Cellular Immunology Laboratory were kindly supported in part by grants from the National Center for Genetic Engineering and Biotechnology, Thailand.

'Breakthrough' Thai HIV vaccine trial controversy.

For the first time ever we know that an HIV vaccine is possible. That’s the significance of the surprise findings in September’s 16 000 person trial in Thailand (the much-maligned RV 144 trial), which showed a 31% reduction in infection risk among participants, say two thrilled top South African researchers. Professor Glenda Gray, head of the perinatal HIV Research Unit at Witwatersrand University says the efficacy of the combination prime-boost vaccine, ‘paves the way for future designs – it’s exciting because it means that a vaccine is attainable’. She and fellow researchers like Professor Salim Abdool Karim, Director of the Centre for the Aids Program of Research of South Africa, (CAPRISA), experience the result as a boost for sagging morale after so many failed trials.

Safety and efficacy of a double-boosted protease inhibitor combination, saquinavir and lopinavir/ ritonavir, in pretreated children at 96 weeks

This study aimed to assess the long-term efficacy, safety and use of therapeutic drug monitoring (TDM) of a double-boosted protease inhibitor (PI) combination, saquinavir (SQV) and lopinavir/ritonavir (LPV/r), in Thai HIV type-1 (HIV-1)-infected children who had failed on reverse transcriptase inhibitors. In total, 50 children from two sites in Thailand were treated with standard dosing of SQV and LPV/r. CD4(+) T-cell count and percentage, viral load (VL; HIV-1 RNA), minimum plasma drug concentrations (C(min)) and drug safety laboratory evaluations were monitored. Virological failure was defined as having two consecutive VL measures >400 copies/ml after week 12. An intention-to-treat analysis was performed. Baseline data were a median age of 9.3 years (interquartile range [IQR] 7.1-11.2), VL 4.8 log(10) copies/ml (IQR 4.5-5.1) and CD4(+) T-cell percentage 7% (IQR 3.0-9.5). CDC classifications were N=4%, A=14%, B=68% and C=14% of participants. Median CD4(+) T-cell percentage and CD4(+) T-cell count increase were 14% (IQR 7-19) and 558 cells/mm(3) (IQR 308-782), respectively (both P<0.001). Overall, 37 (74%) children achieved VL<50 copies/ml with significant differences between sites (90% versus 63%). Over 96 weeks, 10 patients had virological failure. Total cholesterol and high-density lipoprotein increased significantly over time, whereas the triglycerides and low-density lipoprotein did not. Approximately 50% of participants reported no change in body shape, and 33%, 43% and 39% reported fatter arms, face and abdomen, respectively. LPV and SQV C(min) were high and stable over time. Double-boosted SQV+LPV/r was an effective and safe alternative for a second-line regimen in children. Hypercholesterolaemia needs close follow-up. On the basis of the TDM results, PI dose reduction in this population should be considered.

Pharmacokinetics and 48-Week Efficacy of Nevirapine: 400 mg Versus 600 mg per day in HIV–Tuberculosis Coinfection Receiving Rifampicin

We aim here to determine the appropriate dose of nevirapine (NVP) in Thai HIV-tuberculosis (TB)-coinfected patients receiving rifampicin. Thirty-two HIV-infected adults with CD4+ T-cell counts <200 cells/mm3 and active TB, receiving rifampicin for 2-6 weeks were randomized to receive either NVP 400 mg (NVP400) or 600 mg (NVP600) per day plus two nucleoside reverse transcriptase inhibitors; a 2-week NVP lead-in was performed at 200 mg once daily (OD) and 200 mg twice daily, respectively. Plasma NVP levels were determined at weeks 2, 4 and 12. Twelve-hour pharmacokinetics (PK) were obtained (n=20) at week 4. Baseline body weight was comparable. There were more patients with NVP plasma concentration at 12 h (C12) <3.1 mg/l at week 2 in NVP400 than in NVP600 (79% versus 19%, respectively; P=0.002). However, the proportions were comparable at weeks 4 and 12. From week 4, 12 h PK studies showed that NVP400 had lower median NVP area under the plasma concentration-0-12 h (AUC0-12 h, maximum concentration in plasma (Cmax) and C12 than NVP600 (P<0.05). Four patients in NVP600 developed NVP hypersensitivity. At week 48, the median CD4+ T-cell count rise and proportion with viral load <50 copies/ml (intention-to-treat analysis 56% versus 50% and as-treated analysis 75% versus 89%) were comparable. In rifampicin-treated patients, 200 mg NVP OD lead-in led to a significant short-term suboptimal NVP C12 level, while NVP 400 mg lead-in then 600 mg/day was associated with a high rate of NVP hypersensitivity. Forty-eight week efficacy was comparable. Thus, NVP 600 mg/day in rifampicin-treated patients is not recommended.

Immune Reconstitution Inflammatory Syndrome, right sided hemiparesis, in a Thai HIV infected girl with severe immunosuppression

Immune Reconstitution Inflammatory Syndrome, right sided hemiparesis, in a Thai HIV infected girl with severe immunosuppression

Antiretroviral therapy and intestinal microsporidiosis in thai HIV infected patients

Antiretroviral therapy and intestinal microsporidiosis in thai HIV infected patients

Relationship between hyperbilirubinaemia and UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism in adult HIV-infected Thai patients treated with indinavir

To investigate the association between the UGT1A1*6 (G71R) and UGT1A1*28 (promoter (TA)7-repeat) genotypes and hyperbilirubinaemia in Thai patients treated with indinavir, and characterize the inhibition of human UGTs by indinavir in vitro. Ninety-six Thai HIV patients receiving indinavir, 800 mg t.i.d. or 800 mg b.i.d. "boosted" with ritonavir (100 mg b.i.d.), had serum bilirubin levels measured to 24 weeks post-treatment and were genotyped for UGT1A1*6 and UGT1A1*28. The inhibition selectivity and kinetics of indinavir were determined using a panel of recombinant human UGTs. UGT1A1*6 and UGT1A1*28 frequencies in the Thai patients were 10.4% and 15.6%, respectively. Total, conjugated (direct) and unconjugated (indirect) serum bilirubin concentrations increased significantly at 24 weeks of indinavir treatment for all four genotypes, with a trend towards higher levels depending on the number of UGT1A1 mutant alleles; *6/*28 > *6 > *28 > reference. The hazards ratio (HR) for serious hyperbilirubinaemia (total bilirubin > 2.5 mg/dl) at week 24 was statistically significant only in those patients carrying the UGT1A1*6 (HR 2.87) and UGT1A1*6/*28 (HR 11.42) genotypes. The Ki values for indinavir inhibition of UGT1A1 and UGT1A1*6 were 4.1 and 10.7 mumol/l respectively. However, indinavir was also shown to inhibit other human UGTs, notably UGT1A3 and UGT1A7. In contrast to Caucasian HIV-infected patients treated with indinavir, the promoter polymorphism (UGT1A1*28) is of less significance than the coding region (UGT1A1*6) mutation as a risk factor for hyperbilirubinaemia. The Ki values determined for indinavir inhibition of UGT1A1 are consistent with an interaction in vivo, with an additive effect in patients with already impaired bilirubin glucuronidation activity.